The role of polyazamacrocycles in various biomedical applications has increased dramatically over the past few years and the tetraazamacrocyclic structure is becoming an important building block for new pharmaceutical agents. Additionally, polyazamacrocycles are excellent chelants which if available at a low cost could be used in various applications for forming chelates, such as for water treatment systems. As a consequence, the tetraazamacrocyclic structure is becoming a fundamental building block in these compounds. In particular, 1,4,7,10-tetraazacyclododecane ("Cyclen") ##STR1## has proven to be one of the most versatile intermediates used in lanthanide-specific chelating agents which are assuming prominance in compounds used in diagnostic and therapeutic medicine. For example, during recent years the increasing importance of paramagnetic lanthanide chelates as contrast enhancement agents (or contrast agents) for magnetic resonance imaging ("MRI") has resulted in the commercial introduction of two Cyclen based products (Dotarem.TM. by Guerbet and Prohance.TM. by Squibb). Futhermore, numerous companies are engaged in clinical trials involving potential contrast enhancement agents for MRI which are also based on the Cyclen structure. The market for MRI contrast agents is projected to be about US$700 million by 1998 (Frost & Sullivan, 1994) and Cyclen based products are expected to occupy an important position in this market.
At the present time Parrish Chemical Co. is the only advertised bulk supplier of Cyclen (as the tetraazahydrochloride salt), currently quoting a price of US$6,800/pound. This price reflects the difficulty associated with the currently practiced synthetic method to make Cyclen.
Current methodologies for the synthesis of Cyclen include:
J. E. Richman, T. J. Atkins, J. Am. Chem. Soc. 96, 2268-2270 (1974); and PA1 T. J. Atkins, J. E. Richman, W. F. Oettle, Org. Synth. VI(collective volume), 58, 86-97 (1978). PA1 Chem. Abst. 100(13):102774f (Romanian Patent, RO 79987 B, 30 Sep. 1982) which discloses alkyl derivatives; PA1 Chem. Abst. 58:2456a Belgian Patent 613,063, 15 Feb. 1962 to Armour & Co. which discloses other alkyl derivatives; and WO 92/22535, published 12 Dec. 1992, which discloses additional alkyl derivatives. PA1 Chem. Abst. 119(18):194377x; however, in the citation, Z. Anorg. Allg. Chem. 619(7), 1183-95 (1993), from which the abstract was done, actually the closest compound described and made was 1,2-bis(2-imidazoline-2-yl)ethane. PA1 m is 0 or an integer from 1 to 3; PA1 s is 0 or 1; PA1 y is 0 or 1; PA1 z is 0 or 1; PA1 Q is --CH.sub.2 --, --C(O)-- or --CHR; PA1 R is hydrogen, C.sub.1 -C.sub.6 alkyl, --CO.sub.2 H, --CO.sub.2 (C.sub.1 -C.sub.6 alkyl) or phenyl; PA1 R.sup.1 is hydrogen, --CO.sub.2 H, --CO.sub.2 (C.sub.1 -C.sub.6 alkyl), C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkyl substituted by NH.sub.2, NO.sub.2, isothiocyanato, semicarbazido, thiosemicarbazido, maleimido, bromoacetamido or OR.sup.2, phenyl or phenyl substituted by NH.sub.2, NO.sub.2, isothiocyanato, semicarbazido, thiosemicarbazido, maleimido, bromoacetamido or OR.sup.2 ; or PA1 R and R.sup.1 can be taken together to form a phenyl or phenyl substituted by NH.sub.2, NO.sub.2, isothiocyanato, semicarbazido, thiosemicarbazido, maleimido, bromoacetamido or OR.sup.2 ; and PA1 R.sup.2 is hydrogen or C.sub.1 -C.sub.4 alkyl; PA1 which comprises reacting an alkylenepolyamine with a formyl equivalent, such as DMF dimethylacetal, either neat or in a nonaqueous solvent to form the unsubstituted imidazoline (9) of the formula: ##STR4## wherein q is independently 2 or 3; PA1 p is 0 or 1; PA1 t is 0, 1 or 2; and PA1 followed by reacting (9) with: PA1 (A) 1 equivalent of an ethylene oxide or an ethylene carbonate, in an aprotic solvent, to form an alcohol (16) of the formula ##STR5## wherein Q, s, R and R.sup.1 are defined as for Formula (I) and the dotted line represents the optional presence of a bond; when the bond is present, then t is 0, q is 2 to 3, and p is 1; when the bond is absent, then when t is 0, q is 4 or more and p is 1, when t is 1 or more, q is 2 or more and p is 1; PA1 followed by intramolecular amination to form (17) of the formula ##STR6## wherein the various terms are defined as for (16) and X is an anion, e.g., a halide ion; and then either basic or acidic hydrolysis to form a compound of Formula (I); or PA1 (B) an electrophlic substrate, in a polar solvent, optionally in the presence of a non-nucleophilic base, such as potassium carbonate to form (17) of the formula ##STR7## wherein Q, s, R and R.sup.1 are defined as for Formula (I), X is an anion, and the dotted line represents the presence of a bond, t is 0, q is 2 to 3, and p is 1; PA1 and then basic hydrolysis to form a compound of Formula (I); or PA1 (C) an electrophlic substrate, in a polar solvent, optionally in the presence of a non-nucleophilic base, such as potassium carbonate, to form (17) of the formula ##STR8## wherein Q, s, R and R.sup.1 are defined as for Formula (I), X is an anion, and the dotted line represents the presence of a bond, t is 0, q is 2 to 3, and p is 1; PA1 followed by prolonged heating in a polar solvent or by treatment with a peroxide solution to form (18) of the formula ##STR9## wherein Q, s, R and R.sup.1 are defined as for Formula (I) and the dotted lines represent the presence of a double bond, t is 0, q is 2 to 3, and p is 1; PA1 followed by basic hydrolysis to form the urea (19) of the formula ##STR10## wherein Q, s, R and R.sup.1 are defined as for Formula (I) and t is 0, q is 2 to 3, and p is 1; PA1 and then basic hydrolysis under pressure to form a compound of Formula (I); and PA1 separating the desired polyazamacrocycle, i.e. by recrystalization from an aqueous basic solution. PA1 "acidic hydrolysis" means standard hydrolysis conditions in an aqueous system at a pH below about 6.5; for example acetic acid, phosphoric acid, HCl, HBr or H.sub.2 SO.sub.4 (usually from 10 to 20 eqs), usually at an elevated temperature, e.g., a temperature from about 50.degree. to about 120.degree. C., preferably from about 80.degree. to about 120.degree. C. PA1 "C.sub.1 -C.sub.6 alkyl" means straight and branched chained alkyl such as methyl, ethyl, propyl, iso-propyl, tert-butyl (t-butyl), n-hexyl, and includes C.sub.1 -C.sub.4 alkyl. PA1 "alkylenepolyamine" means C.sub.2 -C.sub.18 alkylene N.sub.2 -N.sub.6 polyamine, preferred are C.sub.2 -C.sub.10 alkylene N.sub.2 -N.sub.4 polyamine, more preferred are C.sub.6 alkylene N.sub.4 polyamine; for example EDA, triethylenetetraamine (TETA), N,N'-bis(2-aminoethyl)-1,3-propanediamine, N,N'-bis(3-aminopropyl)-ethylenediamine, diethylenetriamine (DETA), pentaethylenehexaamine or tetraethylenepentaamine. PA1 "ambient temperature" means room temperature or a temperature from about 20.degree. to 26.degree. C. PA1 "aprotic solvent" means a non-nucleophilic solvent having a boiling point range above ambient temperature, preferably from about 25.degree. to about 190.degree. C., more preferably from about 80.degree. to about 160.degree. C., most preferably from about 80.degree. to 150.degree. C., at atmospheric pressure. Examples of such solvents are acetonitrile, DMF, diglyme, THF or DMSO. PA1 "basic hydrolysis" means standard hydrolysis conditions in an aqueous system, at a pH above about 7.5; for example aqueous NaOH or KOH (usually from 3 to 20 eqs), usually at a temperature from about 0.degree. to about 200.degree. C., preferably from about 25.degree. to about 105.degree. C.; with process steps (A) and (B) described above preferably from about 90.degree. to about 100.degree. C.; with process step (C) above to urea (19) at about ambient temperature, preferably from about 25.degree. to about 100.degree. C. PA1 "basic hydrolysis under pressure" means the use of a presure vessel (such as an autoclave at about 120 psi or a Paar bomb) under the other conditions for basic hydrolysis as defined above, such that the temperature for the hydrolysis is maintained at an elevated temperature, e.g., from about 150.degree. to about 210.degree. C., preferably from about 190.degree. to 210.degree. C. PA1 "DETA" means diethylenetriamine. PA1 "diglyme" means 2-methoxy ethyl ether. PA1 "DMF" means N,N-dimethylformamide. PA1 "EDB" means ethylenedibromide or 1,2-dibromoethane. PA1 "EDC" means ethylenedichloride or 1,2-dichloroethane. PA1 "electrophilic substrate" means an organic compound having 1 or 2 electrophilic centers (on carbon atoms) where nucleophilic agents (an amine; primary, secondary or tertiary) can react and contains the R, R.sup.1 and X terms. Examples of such electrophilic carbon centers for substrates are vicinal substrates such as where the C.sub.2 -C.sub.4 alkylidine is substituted with at least two electrophilic groups selected from halogen (Cl, Br, I), sulfonates such as toluene sulfonate, methane sulfonate or trifluoromethane sulfonate, epihalohydrin such as epichlorohydrin or epibromohydrin, 1,3-dihaloacetone such as 1,3-dichloroacetone, oxides such as ethylene oxide or ethylene carbonate, or tosylates, mesylates or triflates of ethylene glycol. Preferred compounds as the substrate include C.sub.2 -C.sub.4 alkylidine (e.g. the 1,1- or 1,2-ethylidine or ethylene oxide) substituted with two dielectrophlic moieties (e.g. dibromo or dichloro groups), such as 1,2-dibromoethylidine. PA1 "elevated temperature" means a temperature above ambient temperature, e.g., from about 30.degree. to about 150.degree. C., preferably from about 60.degree. to about 125.degree. C. PA1 "EO" means ethylene oxide. PA1 "formyl equivalent" means any compound capable of behaving like a formyl moiety [--C(O)--H] under the described process conditions, examples of such compounds are DMF, formic acid, formic acid esters, N,N-dimethylformamidedialkylacetals, trialkylorthoformates, bromoform, chloroform, iodoform, N,N-dialkyl formamides or trihalomethyl acetaldehyde. The "dialkyl" term includes C.sub.1 -C.sub.6 alkyl groups that are either straight or branched chained alkyl groups. Preferred formyl equivalent compounds are DMF and di(C.sub.1 -C.sub.6 alkyl)acetals. PA1 "intramolecular amination" means formation of a carbon to nitrogen bond where the carbon and nitrogen are in the same molecule [i.e., J. March, Advanced Organic Chemistry, 3rd ed., John Wieley & Sons, (1985 ), p 423]. PA1 "non-aqueous solvent" means any organic solvent containing less than 3% water, such as DMF, diglyme, and acetonitrile. PA1 "non-nucleophilic base" means a base which does not act as a nuceolphile in the reactions with the reagents or compounds of this invention; for example, alkali metal carbonates such as potassium carbonate, cesium carbonate, sodium carbonate, or bicarbonates such as sodium bicarbonate. A preferred base is potassium carbonate. PA1 "PEHA" means a mixture of pentaethylenehexaamine isomers containing greater than 30% of the linear isomer. PA1 "peroxide solution" means dilute (about 1-10% w/w) aqueous hydrogen peroxide or aqueous peracids, such as peracetic acid, or derivatives which are capable of releasing peroxide under the reaction conditions, e.g., 10% aqueous H.sub.2 O.sub.2. PA1 "polar solvent" means a solvent which has a dipole moment (.epsilon.) of 2.9 or greater, such as DMF, THF, ethylene gylcol dimethyl ether, DMSO, acetone, acetonitrile, methanol, ethanol, isopropanol, n-propanol, t-butanol or 2-methoxyethyl ether. Preferred solvents are DMF, diglyme, and acetonitrile. PA1 "polar, aprotic solvent" means a polar solvent as defined above which has no available hydrogens to enchange with the compounds of this invention during reaction, for example DMF, acetonitrile, diglyme, DMSO, or THF. PA1 "polyazamacrocycle" means a macrocyclic ring having from 3 to 6 nitrogens present in the backbone of the ring, the other members of the ring are carbon, oxygen, sulfur and silicon, but are preferably carbon. PA1 "prolonged heating" means maintaining a temperature range of from about 80.degree. to about 200.degree. C. for from about 4 to about 48 hours. PA1 "TEPA" means a mixture of tetraethylenepentaamine isomers containing greater than 40% of the linear isomer. PA1 "TETA" means a mixture of triethylenetetraamine isomers containing greater than 50% of the linear isomer which is triethylenetetraamine, (7), and has the structure ##STR11## PA1 "Cyelen" means 1,4,7,10-tetraazacyclododecane, (6), a compound of Formula (I), and has the structure ##STR12## "EDA" means ethylenediamine, (8), and has the structure ##STR13## "1,1'-(1,2-ethanediyl)-bis[4,5-dihydro-1H]-imidazole", (9a), and has the structure ##STR14## "1,2-ethanyl-2-[4,5-dihydro-1H]-imidazole", (10), and has the structure ##STR15## "DETA" means diethylenetriamine, (1), and has the structure ##STR16## "TEPA" means tetraethylenepentaamine, (11), and has the structure ##STR17## "1,1'-(2,2'-diethylamine)-bis[4,5-dihydro-1H]-imidazole", (12), and has the structure ##STR18## "PEHA" means pentaethylenehexaamine, (13), and has the structure ##STR19## "1,2-ethanediyl-bis(1,2-ethanyl-2-[4,5-dihydro-1H]-imidazole), (14), and has the structure ##STR20##
The currently practiced methodology for the synthesis of Cyclen [J. E. Richman, T. J. Atkins, J. Am. Chem. Soc. 96, 2268-2270 (1974)] involves a multistep protection-deprotection strategy as shown in the following Scheme A. ##STR2##
The conventional synthesis of tetraazamacrocyclic ligands involves the reaction of two segments of the target macrocycle in a polar, aprotic solvent, with the most used methodology being the Richman and Atkins' synthesis [J. E. Richman, T. J. Atkins, J. Am. Chem. Soc. 96, 2268-2270 (1974)]. In this procedure, one precursor is a preformed salt of a tritosylamide and the other precursor contains sulfonate esters as the leaving groups. (See Scheme A above.) This method has been the one most cited in the literature to prepare saturated polyazamacrocyles containing 3-12 nitrogen atoms.
Final isolation of the macrocycle requires harsh conditions to remove the protecting groups (e.g. tosyl or methanesulfonyl groups). These conditions involve either the use of 97% sulfuric acid or 33% HBr, acetic acid and phenol.
This methodology is adequate, provided that great care is dedicated to the use of very pure, dry starting material. The overall process is tedious, time consuming, low yielding (.about.20-30% based on the starting amine) and an abundace of tosylate or mesylate salts are generated as waste. Clearly, this described process is time consuming and costly to make commercial quantities of the desired compound.
Another approach which has been tried towards the synthesis of large polyazamacrocycles (meaning those having at least a 14 membered ring) has been the use of metal ion promoted (template) reactions, developed in the early 1960's. Many polyazamacrocycles in their complexed form have been obtained by condensing glyoxal and a polyamine in the presence of a metal ion, mainly Ni(II) and Cu(II). The metal ion can aid in one of two ways: (1) complex and sequester the polyazamacrocyclic product from the reaction equilibrium mixture (in this way the formation of a macrocycle is promoted as its metal complex); or (2) the metal ion influences the steric course of the condensation such that formation of the cyclic product is facilitated [A. Bianchi, M. Micheloni, P. Paoletti, Coor. Chem. Rev. 110, 17 (1991)]. Regardless of how the metal ion functions, the application of such chemistry to the synthesis of thirteen-membered (or less) polyazamacrocycles has not been successful, probably due to the incompatibility of the metal size and the eventual cavity size of the desired macrocycle.
Previous synthesis of derivatives of 1,1'-(1,2-ethanediyl)-bis[4,5-dihydro-1H]-imidazole include:
A citation which incorrectly indicates that 1,1'-(1,2-ethanediyl)-bis[4,5-dihydro-1H]-imidazole was prepared is:
Clearly, it would be advantageous to have a cheaper, less time consuming process to make the desired polyazamacrocycles. Some of the ways by which these results could be attained are by using less costly starting materials not requiring the Richman-Atkins protection-deprotection method [J. Am. Chem. Soc. 96, 2268-2270 (1974) and Org. Synth. VI(collective volume), 58, 86-97 (1978)], and by increasing the overall yield of the process.